Bench to Bedside: From the Laboratory to the Pharmacy

OSU-10079 – A Phase 1 Study of Lenalidomide Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Patients with Select High-Risk Hematological Malignancies

Hypothesis: The use of lenalidomide post-transplant in patients with high-risk acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL), or chronic lymphocytic leukemia (CLL) will be safe and will not significantly increase the risks of graft-vs-host disease (GVHD), graft rejection, or infection. If efficacious, this therapy could promote durable remission in patients who are treated with reduced-intensity conditioning regimens and are otherwise destined to relapse.

Rationale: Lenalidomide belongs to class of compounds called immunomodulatory drugs. It was derived from thalidomide and selected for clinical development after it was found to be more stable and 50,000-fold more potent at inhibiting tumor-necrosis factor alpha than thalidomide.

Lenalidomide has multiple potential antitumor mechanismso f action, but which mechanisms are responsible for clinical activity in patients who respond to therapy is unclear, and they may differ according to tumor type. These mechanisms include the modulation of cytokines and of T cells and natural-killer (NK) cells, the inhibition of blood-vessel growth, and direct effects on tumor cells.

Studies show that allogeneic blood or marrow transplantation (alloBMT) benefits many patients with advanced hematological malignancies. For patients in remission, it often offers the best opportunity for long-term disease-free survival. For some patients who have relapsed or become refractory to conventional therapy, it is the only therapeutic option associated with durable remission.

More recently, reduced-intensity conditioning regimens have been used prior to transplantation to reduce transplant-related complications, toxicity and mortality. They allow donor-marrow engraftment to occur without the widespread tissue damage associated with standard myeloablative conditioning. Unfortunately, recent data suggest that reduced-intensity conditioning is associated with higher rates of disease relapse and chronic GVHD. Thus, while a reduced-intensity conditioning regimen allows most patients to survive the early post-transplant period and achieve initial engraftment of donor cells, they are often left with residual disease that eventually proliferates before they can develop an adequate immune response from donor-derived T and NK cells.

In this dose-escalation trial, we evaluate whether the addition of the immunomodulatory agent lenalidomide will mitigate relapse risk following reduced-intensity conditioning alloBMT. Detailed correlative studies will assess lenalidomide’s effects on immunologic response and specific anticancer activity. If this clinical approach proves feasible, we will proceed to a follow-up phase II study examining this treatment in each of the disease groups studied.

Eligibility: Patients with high-risk AML, NHL or CLL will be divided into three strata based on disease subtype. Each stratum has separate inclusion criteria, but all patients must meet the following criteria: be four weeks or more from prior chemotherapy (excluding steroids), radiation, or radioimmunoconjugate therapy; age 18 to 75; ECOG performance status 0-2; DLCO greater than 40 percent with no symptomatic pulmonary disease; LVEF by Echo or MUGA 30 percent; HIV negative; creatinine clearance of 60 cc/min according to the Cockroft-Gault equation; total bilirubin less than 2 mg/dL; AST/ALT less than or equal to 2.5 x ULN; no uncontrolled infection or diabetes mellitus; eligible donor identified.

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